A product of the Sliema Wanderers nursery, Mifsud made his debut in the premier league in season 1997-98. In 2001 Michael moved to Germany and joined Kaiserslautern.
In the winter of 2004 Michael was released from Kaiserslautern, he returned back to his country and re-signed for Sliema Wanderers and helped them retain the Maltese league championship. In summer of 2004 he joined Norwegian Premier League club Lillestrom. In season 2006 he became the club's top scorer with 11 goals in 19 appearances.
On January 10 2007, Michael Mifsud signed a two-and-a-half year contract with Coventry City. In September 2007, in the third round of the Carling Cup, Michael Mifsud scored two important goals to give Coventry an unexpected 2–0 victory over Premier League champions, Manchester United. With Coventry City Mifsud scored 16 goals in 86 matches. On February 2, 2009, Mifsud joined Barnsley on loan until the end of the season.
On June 30, 2009, Michael was released from Barnsley City after his contract with the club had expired.
On March 10, 2010 Michael joined Valletta FC. During his stay with Valletta he helped the Whites in winning the National League 100 Anniversary Cup and the FA Trophy.
In February 2011, Michael joined Qormi F.C. and signed a contract till the end of the season. He made a total of 5 appearances and scored 7 goals.
Michael re-joined Valletta F.C. in July 2011, he signed a four-year deal. During his spell with Valletta F.C. Michael made a total of 47 appearances and scored a total of 28 goals. He left Valletta FC in 2013 and travelled to Australia and joined Melbourne Heart. Mifsud made a total of 14 appearances and scored a goal.
In 2014, Michael returned to Malta and signed a contract with his home-town team Sliema Wanderers. Michael made a total of 32 appearances with the Wanderers and scored five goals.
Mifsud returned back with Valletta F.C. in January 2016, he signed a two and a half year deal with Valletta till May 2018.